Retrospective Evaluation of the Impact of Dose Escalation Using Pre-operative Simultaneous Integrated Boost Volumetric Modulated Arc Therapy on the Outcome of Locally Advanced Rectal Cancer Patients

Evaluating the outcome of pre-operative simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) concomitant with capecitabine in patients diagnosed with locally advanced rectal cancer (LARC) at King Faisal Specialist Hospital and Research Centre (KFSH&RC), Riyadh, Saudi Arabia, during the period January 2013–December 2019. A total of 134 patients were enrolled. The median age at diagnosis was 59 years. All patients received pre-operative concurrent chemo-radiation therapy (CCRT) using SIB-VMAT with oral capecitabine. Neoadjuvant chemotherapy was administered prior to CCRT in 32 patients (23.9%). The dose of radiation was 55 Gy in 94 patients (70.1%), while 40 patients (29.9%) received 50 Gy. All patients completed the CCRT treatment without breaks. No records of acute and late grade III and IV toxicities. Curative surgery was performed in all patients with a median interval of 11 (6–52) weeks between the end of CCRT and the date of surgery. No reported 30-day postoperative mortality and no grade III and IV Clavien-Dindo complications. PCR was reported in 26 patients (19.4%), while pathologically negative nodes (pN0) were achieved in 103 patients (76.9%). Adjuvant chemotherapy was utilized in 57 patients (42.5%). The 5-year local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were 93.2%, 67.1%, and 87.3%, respectively. Only tumor regression grade (TRG) was significantly correlated with LRFS, (p value 0.043). On multivariate analysis, only TRG and achievement of pN0 were significantly correlated with DFS (p value < 0.001). Dose escalation utilization (SIB-VMAT) in the pre-operative treatment of LARC is well tolerated and provides effective local control.


Background
In the year 2020, colorectal cancer (CRC) was the 3rd commonly diagnosed malignancy worldwide in men after lung and prostate cancer and the 3rd leading cause of cancer mortality after lung and liver cancer.In women, CRC is the 2nd malignancy in incidence after breast cancer and the 3rd leading cause of mortality after breast and lung cancer [1].
In Saudi Arabia, CRC is the most commonly diagnosed cancer in men and the third in women with 1659 new reported cases in 2016, representing about 13% of all diagnosed cancers [2].
Radiation therapy has a well-established role in the management of locally advanced rectal cancer (LARC) patients with reduction in the incidence of local recurrence rate with near complete shift from adjuvant to the neo adjuvant era due to the improved local control rate and less toxicity for neo adjuvant over adjuvant radiation therapy [3].
New radiation techniques such as intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) have been frequently used over the last 20 years for the treatment of rectal cancer.They are associated with better dose conformity, better sparing of organs at risk (OARs), and lower toxicity in comparison to the more traditional techniques (2D and 3D conformal radiation therapy [3DCRT]) [4,5].
The addition of concomitant chemotherapy to preoperative radiotherapy (CCRT) resulted in a significant increase in local control rate with a slight increase in acute toxicity, but there was no increase in postoperative morbidity.However, no significant improvement in overall survival was observed in any study [6].
Using the standard CCRT approach (radiation therapy dose of 45-50.4 Gy/25-28 fractions in 2 phases concomitant with 5-FU-based chemotherapy), only about 11-18% of patients will achieve a pathological complete remission (pCR) [7][8][9][10][11][12].As this group of patients shows a better overall prognosis compared to patients with less or no response [13], several strategies have been investigated to improve the pCR rate including radiation dose escalation that could be achieved through the addition of more fractions in conventional fractionation, utilization of altered fractionation regimes, or addition of a brachytherapy boost.The reported pCR rates with dose escalation ranged from 0 to 50% with an average of 22% [14].
The simultaneous integrated boost (SIB)-IMRT/VMAT techniques allow the simultaneous delivery of different dose levels to different target volumes within a single treatment fraction which allows for radiation therapy dose intensification.Many studies evaluated the role of radiation dose intensification utilizing the SIB-IMRT technique along with concurrent 5-FU-based chemotherapy in the treatment of LARC.It found a strong correlation between increased radiation dose and higher pCR rates, along with an acceptable toxicity profile [15].
In our study, we retrospectively evaluated the outcome of patients diagnosed with LARC who were treated with pre-operative (SIB-VMAT) technique concomitant with capecitabine.

Methods
The medical records of patients diagnosed with LARC who were treated with pre-operative SIB-VMAT at the Oncology Center at King Faisal Specialist Hospital & Research Centre in Riyadh, Saudi Arabia (KFSH&RC), were retrospectively evaluated.Data retrieved included demographic data, clinical (c) TN stage, tumor size (cranio-caudal dimension), tumor distance from the anal verge (AV distance), circumferential radial margin (CRM) status on magnetic resonance imaging (MRI) (considered positive if tumor is less than 1 mm away from the mesorectal fascia), pre-operative chemotherapy data, radiation therapy data, surgical data, postoperative morbidity and mortality, pathological TN stage (pTN), tumor regression grade (TRG), actual number of retrieved lymph nodes, adjuvant chemotherapy data, late toxicity data, site and date of recurrence, and status (alive without disease, alive with disease, or dead).
All patients diagnosed with rectal cancer underwent full laboratory workup including tumor markers; full colonoscopy assessment; rigid proctosigmoidoscopy; endorectal ultrasound (ERUS); endoscopic guided biopsy; computed topography (CT) of the chest; abdomen, and pelvis; and magnetic resonance imaging (MRI) of the pelvis.
All the patients were evaluated and managed by a multidisciplinary team that included colorectal surgeons, medical and radiation oncologists, abdominal radiologists, gastrointestinal pathologists, enterostomal therapists, and hereditary colorectal tumor registrars.
All the patients included in this study were diagnosed with LARC and satisfied the following inclusion criteria: age ≥ 18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; pathologically proven adenocarcinoma for rectal lesion up to 15 cm from the anal verge; adequate hematological, renal, and hepatic functions; (c) T3, T4, and/or lymph node positive (cN +) by MRI pelvis and/or ERUS; and no evidence of distant metastatic disease.
All patients were planned to receive pre-operative CCRT (SIB-VMAT 55 Gy/25 fractions/5 weeks) concomitant with oral daily capecitabine 825 mg/m2/12 h 5 days per week/5 weeks.The dose of radiation therapy was reduced to 50 Gy in some patients when our acceptance criteria for OARs were not met mostly due to the small bowel.For more details about radiation therapy plans, volumes, and acceptance criteria, please review our previous published study [16].
Neoadjuvant chemotherapy for an average of 4 months was used in our center in patients with cT4B and/or upfront unresectable disease to improve tumor surgical resectability.Adjuvant chemotherapy was used for those patients who did not receive neoadjuvant chemotherapy and did not achieve PCR post CCRT with pathologically (pT3, T4) and/or had pathologically node-positive disease (pN +).Different regimens were utilized as neoadjuvant or adjuvant chemotherapy (including FOLFOX, CAPEOX, and capecitabine).The type and number of chemotherapy regimens were decided by medical oncologist based on several factors including age, performance status (PS), co-morbidities, and TN stage, in addition to the choice of the patient.
All the patients were followed once weekly during CCRT to assess for acute toxicity.Acute toxicity was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [17].In order to assess response to CCRT and exclude metastasis, a repeated MRI and CT were performed for all patients prior to surgical treatment.
Surgery was performed after an elapsed period of 6-12 weeks post CCRT.The 30-day postoperative complication rates were evaluated according to the Clavien-Dindo grading system [18].
Tumor regression grade (TRG) was assessed according to the American Joint committee on Cancer (AJCC) staging manual, 8th edition, and the College of American Pathologists (CAP) guidelines as modified by Rayan et al. [19].The patients in our study were divided into two groups for comparison (good responders including grade 0,1) and poor responders (grade 2,3).
All patients were kept under regular follow-ups with medical oncology and/or colorectal surgery teams.
Follow-up intervals were as follows: every 3-4 months during the first 2 years, every 6 months during the 3rd-5th year, and then annually.Follow-up included history; physical examination; complete laboratory workup with tumor markers; and CT of the chest, abdomen, and pelvis.Colonoscopy is usually performed at 1 and 3 years after the initial colonoscopy and then subsequently every 5 years as long as there are no clear indications to be conducted earlier.
Primary end point for our study was 5-year local recurrencefree survival (LRFS).Secondary end points included 5-year disease-free survival (DFS), 5-year overall survival (OS), and late toxicity.

Statistical Analysis
Statistical analysis was conducted utilizing IBM SPSS ® Statistics version 26 (IBM ® Corp., Armonk, NY, USA).Quantitative variables were described as median and range.Qualitative variables were described as numbers and percentages.Pearson's Chi-square test or Fisher's exact test was used to test the relationship between qualitative variables.
DFS was calculated from the surgery date until the date of documented recurrence, death, or last follow-up.OS was calculated from the date of diagnosis until the date of death or date of last follow-up.Survival analysis was performed utilizing the Kaplan-Meier method, and a comparison between two survival curves was conducted using the logrank test.
Multivariate analysis was performed using the Cox-proportional hazard regression model with the forward likelihood ratio method for the factors affecting survival on univariate analysis.Hazard ratio (HR) with 95% confidence interval (CI) was used for risk estimation.All tests were two-tailed.A p value < 0.05 was considered significant.

Results
A total of 134 patients were included in this study; the median age at diagnosis was 59 (25-102) years; detailed patient and tumor characteristics are listed in Table 1.The details of radiation and chemotherapy treatments are listed in Table 2.All patients completed the CCRT treatment course with no breaks.There were no incidents of grade III and IV acute or late toxicities.The details of acute and late toxicities are listed in Table 3. Curative surgery was performed in all patients with a median interval of 11  weeks between the end of CCRT and the date of surgical intervention.There was no 30-day postoperative mortality.There were also no Clavien-Dindo grade III and IV postoperative complications.Details about the type of surgery are listed in Table 2. Pathological response to treatment is listed in Table 4. PCR was reported in 26 patients (19.4%), while pN0 was achieved in 103 patients (76.9%).
In relation to LRFS, only TRG was significantly correlated with LRFS in univariate analysis (p value 0.043; Table 5).
In relation to DFS, univariate analysis included pathological response to treatment (TRG), pathological node status, clinical stage, tumor size, and CRM.All achieved a significance level of p value < 0.05.When these variables were included in a multivariate analysis, only TRG (good responders) and pN0 achieved significance at p value < 0.05 (Table 5 and Fig. 3).
In relation to OS, both pathological response to treatment (TRG) and pathological node status (pN0) correlated significantly in univariate analysis.Only pN0 achieved significance correlation in the multivariate analysis (Table 5 and Fig. 4).

Discussion
In the current study, we aim to evaluate the long-term outcome (including 5-year LRFS, DFS, and OS) in addition to late toxicity for our patients with locally advanced rectal cancer treated with the pre-operative SIB-VMAT concurrent with chemotherapy, contrary to our previous published paper [16], in which we assess the feasibility, response rate evident by PCR rate, and acute toxicity only.
In the current study, the PCR rate achieved was 19.4%.This is higher than the that reported before in many studies using neoadjuvant CCRT in conventional fractionations: Roh et al. [20], Park et al. [21], and Sauer et al. [22], where the PCR rate were 15%,17%, and 8% respectively.Our current study PCR also is 2.5 times higher than our earlier PCR rate of 7.6% as reported in a previous study from our institution [23].The main difference between the current study and the previous one from our institution is the dose and the technique of pelvic radiation: the SIB-VMAT technique was used in the current study with a total dose of 50-55 Gy in 25 fractions compared to the 3DCRT technique in the previous study with a dose of 50.4 Gy given over 28 fractions in 2 phases (26% of patients received radiation therapy only).This difference was not so evident between SIB-IMRT and 3DCRT techniques in another study conducted by Bong et al., where the incidence of PCR was 9% vs 7%, respectively [24].The PCR rate in our study was slightly lower than that achieved by Zhu et al. [25] (19.4% vs 23.7% respectively).That difference might be attributed to the use of oxaliplatin (weekly) in addition to capecitabine concomitant with radiation therapy followed by one cycle of CAPEOX in all patients pre/-operatively in Zhu et al. [25] study.
Local recurrence (LR) occurred in our study only in 8 (5.9%) patients with a 5-year LRFS of 93.2%.This is much lower than that in the study conducted by Zhu et al. [25] Fig. 2 OS for whole patients' population where the 3-year local recurrence rate was 14.6% despite the higher PCR rate achieved by Zhu et al. at 23.7% vs 19.4% in our study.This might be attributed to the fact that the surgery in our study was conducted by board-certified colorectal surgeons and not general surgeons.In comparison to Sibel et al. [26], where the 5-year local control (LC) rate was 75.5% vs. 93.2% in our study, one might postulate that the higher radiation dose of 55 Gy was used in 70% of cases in our study vs dose of 50.4 GY used in Sibel et al. study [26].
Only TRG was significantly correlated with LRFS in univariate analysis; this supports the prognostic significance of PCR that was shown before in studies [10,11].
The 3-year DFS and OS of 69.3% and 95.3%, respectively, in this study are higher than the 3-year DFS and OS of 63.8% and 77.4%, respectively in Zhu et al.'s [25] study.That might be attributed to the better local control rate in our study.The same applies to the better 5-year DFS and OS in our study of 67.1% and 87.3%, respectively, in comparison to those in the study conducted by Sibel et al. [26], where the 5-year DFS and OS were 66.7% and 73.1%, respectively.
By comparing our 5-year LR rate, DFS, and OS with those in studies utilizing neoadjuvant CCRT in conventional fractionation, we found better 5-year LR rate of 5.9% vs 10.7% and 6% in Roh et al. [20] and Sauer et al. [22] respectively, with comparable 5-year DFS of 67.1% vs 64.7% and 68% in Roh et al. [20] and Sauer et al. [22] respectively, with better 5-year OS of 87.3% in current study vs 74.5% and 76% in Roh et a.l [20] and Sauer et al. [22] respectively.Moreover, in the current study, we have better 3-year DFS of 69.3% and 5-year OS of 87.3% in comparison to 67% and 81% respectively noted in Alzahrani et al. study [23].That improvement in LRFS, DFS, and OS in our study in comparison to that of the above-mentioned studies is probably attributed to the better PCR rate achieved in our study.
The lungs were the most common site of relapse in 19/32 (59.3%) patients.This is compatible with the review Fig. 3 Factors significantly correlate with DFS on multivariate analysis.A TRG (good responders grade 0,1 vs poor responders grade 2,3).B Pathological node status (pN0 vs pN +) conducted by Guraya [27], where he found pulmonary recurrence is commonly associated with rectal tumors, while liver metastasis is commonly associated with colon cancer.
Only TRG and achievement of pN0 were independent prognostic variables with regard to DFS on multivariate analysis.This was similarly noted by Zhu et al. in their study [25] where TRG was an independent prognostic factor for DFS.
In addition to the improved outcome in our study in comparison to the above-mentioned studies using conventional fractionations, we found also significant improvement in toxicity profile as no patients in the current study developed grade III or IV acute toxicity and only 40 (29.8%)patients developed grade I and II toxicities, in comparison to incidence of acute toxicities ≥ grade III of 52%, 15%, and 27% in Roh et al. [20], Park et al. [21], Sauer et al. [22], respectively.The incidence of acute toxicities in our study was found also to be lower than reported in other studies using SIB-IMRT; in Zhu et al.'s [25] study, the incidences of acute grade III hematologic toxicity, diarrhea, and radiation dermatitis were 3.8%, 10.3%, and 17.9%, respectively.In another study conducted by Sibel et al. [26], the incidences of grade III diarrhea and cystitis were 10% and 7.5% respectively.The incidence of late toxicity also was very low in our study.Late toxicity developed in only 10 (7.4%) patients with no reported grade III or IV toxicity.That reduction in the incidence of acute and late toxicities in our study with no incidents of grade III or IV toxicities might be attributed to the strict dose constraints for OARs especially to the small bowel.The irradiated volumes were limited to 0 and < 20 cc in doses higher than 50 and 45 Gy, respectively [28].In 40 patients (29.8%), we were not able to achieve these bowel limitations, so we decreased the used radiation dose to 50 Gy instead of 55 Gy.
The main two limitations of our study is the relatively small number of patients and the retrospective design.

Conclusion
Dose escalation using (SIB-VMAT) in the pre-operative treatment of LARC is well tolerated and offers effective long-term local control.
Author Contribution Material preparation, data collection, and analysis were performed by Ahmed Elashwah, Abdullah Alsuhaibani, and Ahmed Awad (A.E, A.S, and A.A respectively).Surgical management and postoperative follow-up were done by Alaa Abduljabbar, Nasser Alsanea, Samar Alhomoud, and Luai Ashari (A.J, N.A, S.A, L.A respectively).The radiation therapy indications, treatment planning, and follow-up during radiation therapy are done by Abdullah Alsuhaibani, Ahmed Elashwah, and Mohammed Alshabanah (A.S, A.E, and M.A respectively).All chemotherapy indications and treatment were decided by Shouki Bazarbashi, Ali Aljubran, and Ahmed Alzahrani (S.B, A.JUB, Ah.Z respectively).All the histopathological tests and examinations were performed by Hadeel Almanea and Hussah Alhussini (H.A, Hu.A respectively).The first draft of the manuscript was written by Ahmed Elashwah (A.E) and all authors commented on previous versions of the manuscript.All authors read and approved the final manuscript.

Table 1
Patients and tumor characteristics

Table 2
Treatment characteristics

Table 3
Reported acute and late toxicities *Many patients developed more than one acute toxicity **One patient developed both GIT and genitourinary late toxicity

Table 4
Response Fig. 1 DFS for whole patients' population

Table 5
Correlations between multiple parameters with LRFS, DFS, and OS in univariate and multivariate analysis